This application is a national-stage entry under 35 U.S.C. xc2xa7371 of PCT/JP99/00072, filed Jan. 11, 1999.
The present invention relates to new benzamide derivatives and salts thereof which are useful as medicaments.
Some benzamide derivatives have been known as vasopressin antagonist, for example, in PCT International Publication Nos. WO 91/05549 and WO 95/29152, EP Publication No. 0620216, and Japanese Patent Unexamined Publication Nos. 154765/1992 and 221476/1997.
This invention relates to new benzamide derivatives and salts thereof.
More particularly, it relates to new benzamide derivatives and salts thereof which exhibit activities such as vasopressin antagonistic activity, to pharmaceutical compositions comprising the same and to methods for the treatment and/or prophylaxis of cerebrovascular disease (e.g. cerebral edema, cerebral infarction, etc.), depressant, anxiety and the like in human beings and animals.
One object of this invention is to provide new and useful benzamide derivatives and salts thereof which possess the aforesaid activities.
Another object of this invention is to provide processes for the preparation of said benzamide derivatives and salts thereof.
A further object of this invention is to provide pharmaceutical compositions comprising, as an active ingredient, said benzamide derivatives or pharmaceutically acceptable salts thereof.
Still further object of this invention is to provide methods for the treatment and/or prophylaxis of the aforesaid diseases in human beings and animals, using said benzamide derivatives and pharmaceutically acceptable salts thereof.
The object benzamide derivatives of this invention are new and can be represented by the following formula (I): 
wherein
A is an optionally substituted heterocyclic group;
R is a lower alkoxy;
Z is Cxe2x95x90O or CH2; and
B is a saturated or unsaturated condensed ring group selected from the group consisting of benzazepinyl, benzodiazepinyl, pyridoazepinyl, pyridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenzoxazepinyl and indolinyl, each member being optionally substituted,
preferably, by the following formula (II): 
wherein A, B, R and Z are each as defined above, or a salt thereof.
The object compound (I) of the present invention can be prepared according to the following reaction schemes. 
(wherein B, Z, and R are each defined above.) 
(wherein A1 is a heterocyclic group substituted with an N-protective group, a protected amino or a substituent having protected amino, B1 is any one of benzazepinyl, thienoazepinyl, benzodiazepinyl, pyridoazepinyl, pyridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenzoxazepinyl and indolinyl, which is substituted with an N-protective group, a protected amino or a substituent having protected amino, A2 is a heterocyclic group not substituted with an N-protective group or substituted with amino or a substituent having amino, B2 is any one of benzazepinyl, benzodiazepinyl, pyridoazepinyl, pryridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenzoxazepinyl and indolinyl, which is not substituted with an N-protective group or substituted with amino or a substituent having amino, and Z and R are each defined above.) 
(wherin B3 is any one of benzazepinyl, benzodiazepinyl, pyridoazepinyl, pyridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenzoxazepinyl and indolinyl, which is substituted with =O, B4 is any one of benzazepinyl, benzodiazepinyl, pyridoazepinyl, pyridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenzoxazepinyl and indolinyl, which is substituted with hydroxy, and A, Z and R are each as defined above.) 
(wherein A3 is a heterocyclic group substituted with phthaloylaminoalkyl, A4 is a heterocyclic group substituted with aminoalkyl, and B, Z and R are each defined above.) 
(wherein A5 is a heterocyclic group substituted with amino or aminoalkyl, A6 is a heterocyclic group substituted with (di)alkylamino or (di)alkylaminoalkyl, and B, Z and R are defined above.) 
(wherein A8 is a heterocyclic group substituted with protected hydroxyalkyl, A9 is a heterocyclic group substituted with hydroxyalkyl, and B, Z and R are each as defined above.) 
(wherein B5 is saturated or unsaturated benzothiazenpinyl, B6 is a saturated or unsaturated S-oxo-benzothiazepinyl, and A, Z and R are each as defined above.) 
(wherein B7 is a saturated or unsaturated S,S-dioxo-benzothiazepinyl, and A, Z, B6 and R are each as defined above.)
Suitable salts of the object compound [I] are pharmaceutically acceptable, conventional non-toxic mono- or di-salts and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt), an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate), an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate) and a salt with an amino acid (e.g. arginine salt, aspartic acid salt, glutamic acid salt).
Suitable examples of the various definitions to be included within the scope of the invention, which are given in the description of the present specification, are explained in detail in the following.
The term xe2x80x9clowerxe2x80x9d is intended to mean a group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise provided.
Suitable xe2x80x9clower alkoxyxe2x80x9d includes straight or branched ones such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 2-ethylpropoxy and hexoxy, in which the preferred one is (C1-C4)alkoxy.
Suitable xe2x80x9cheterocyclic groupxe2x80x9d defined for A of the formula (I) includes saturated or unsaturated, monocyclic or polycyclic group such as unsaturated 3 to 8-membered (more preferably 5 to 7-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, azepinyl (e.g. 1H-azepinyl), pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl), tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl), etc.;
saturated 3 to 8-membered (more preferably 5 to 7-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, perhydroazepinyl (e.g. perhydro-1H-azepinyl), pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, quinoxalinyl, imidazopyridyl (e.g. imidazo[4,5-c]pyridyl), tetrahydroimidazopyridyl (e.g. 4,5,6,7-tetrahydroimidazo[4,5-c]pyridyl), etc.;
saturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, 7-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.2.2]-nonanyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl (e.g. 2-morpholinyl, 3-morpholinyl, 4-morpholino), sydnonyl, etc.;
unsaturated condensed heterocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl), dihydrothiazinyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.;
unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.;
saturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s);
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom and 1 or 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.;
unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc.; and
unsaturated condensed heterocyclic group containing an oxygen atom and 1 or 2 sulfur atom(s), for example, benzoxathiinyl, etc.
Suitable xe2x80x9csubstituent(s)xe2x80x9d of xe2x80x9cheterocyclic groupxe2x80x9d includes lower alkyl optionally substituted with hydroxy, protected hydroxy, amino, protected amino, alkyl-substituted amino, lower alkoxy, acylamino or N-containing heterocyclic group; N-protective group; lower alkoxy; haloalkyl; amino optionally substituted with lower alkyl, acyl or N-protective group; carbamoyl optionally substituted with lower alkyl; acyl; acylamino; aminoalkylamino optionally substituted with lower alkyl or N-protective group; and N-containing heterocyclic group optionally substituted with lower alkyl, amino optionally substituted with lower alkyl or N-protective group,
Suitable xe2x80x9clower alkylxe2x80x9d and xe2x80x9clower alkylxe2x80x9d moiety in xe2x80x9coptionally substituted with lower alkylxe2x80x9d include straight or branched (C1-C6)alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, 2-ethylpropyl and hexyl, in which the preferred one is (C1-C4)alkyl.
Suitable xe2x80x9clower alkoxyxe2x80x9d and xe2x80x9clower alkoxyxe2x80x9d moiety in xe2x80x9coptionally substituted with lower alkoxyxe2x80x9d include straight or branched (C1-C6)alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 2-ethylpropoxy and hexoxy, in which the preferred one is (C1-C4)alkoxy.
Suitable xe2x80x9cN-protective groupxe2x80x9d, xe2x80x9cN-protective groupxe2x80x9d moiety in xe2x80x9coptionally substituted with N-protective groupxe2x80x9d and amino-protective group of xe2x80x9ca protected aminoxe2x80x9d include aryl(lower)alkyl such as mono- or di- or triphenyl(lower)alkyl (e.g. benzyl, phenethyl, 1-phenylethyl, benzhydryl, trityl) and acyl as explained hereinbelow.
Suitable xe2x80x9cacylxe2x80x9d, xe2x80x9cacylxe2x80x9d moiety in xe2x80x9coptionally substituted with acyl or acylaminoxe2x80x9d and xe2x80x9cacylxe2x80x9d moiety in xe2x80x9cacylaminoxe2x80x9d include aliphatic acyl, aromatic acyl, arylaliphatic acyl and heterocyclic-aliphatic acyl derived from caboxylic acid, carbonic acid, carbamic acid or sulfonic acid.
Suitable examples of the acyl group thus explained are lower alkanoyl (e.g. formyl, acetyl, propionyl, hexanoyl, pivaloyl), mono(or di or tri)halo(lower)alkanoyl (e.g. chloroacetyl, trifluoroacetyl), lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl), mono(or di or tri)halo(lower)alkoxycarbonyl (e.g. chloromethoxycarbonyl, dichloroethoxycarbonyl, trichloroethoxycarbonyl), aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl), aryl(lower)alkanoyl such as phenyl-(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl), aryloxycarbonyl (e.g. phenoxycarbonyl, naphthyloxycarbonyl), aryloxy(lower)alkanoyl such as phenoxy(lower)alkanoyl (e.g. phenoxyacetyl, phenoxypropionyl), arylglyoxyloyl (e.g. phenylglyoxyloyl, naphthylglyoxyloyl), aryl(lower)alkoxycarbonyl which may have suitable substituent(s) such as phenyl(lower)alkoxycarbonyl which may have nitro or lower alkoxy (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, p-nitrobenzyloxy-carbonyl, p-methoxybenzyloxycarbonyl), thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, triazolylacetyl, thiadiazolylacetyl, thienylpropionyl, thiadiazolylpropionyl, lower alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, pentylsulfonyl, butylsulfonyl), arylsulfonyl (e.g. phenylsulfonyl, tolylsufonyl, xylylsufonyl, naphthylsufonyl) and aryl(lower)alkylsufonyl such as phenyl(lower)alkylsufonyl (e.g. benzylsufonyl, phenethylsufonyl, benzhydrylsufonyl).
Examples of preferable xe2x80x9cprotected aminoxe2x80x9d are aryl(lower)alkylamino, lower alkanoylamino and lower alkoxycarbonylamino, more preferable ones are triphenyl(Ci4)alkylamino, (C1-C4)alkanoylamino and (C1-C4)alkoxycarbonylamino, and the most preferable ones are tritylamino, formamido, acetamido and tert-butoxycarbonylamino.
Suitable xe2x80x9calkylxe2x80x9d moiety in xe2x80x9calkyl-substituted aminoxe2x80x9d, xe2x80x9chaloalkylxe2x80x9d and xe2x80x9caminoalkylaminoxe2x80x9d include straight or branched (C1-C6)alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, 2-ethylpropyl and hexyl, in which the preferred one is (C1-C4)alkyl.
Examples of preferable xe2x80x9calkyl-substituted aminoxe2x80x9d are methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-tert-butylamino, dipentylamino, dihexylamino or the like.
Examples of preferable xe2x80x9chaloalkylxe2x80x9d are fluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 4-fluorobutyl, 5-fluoropentyl, 6-fluorohexyl, chloromethyl, 1-chloroethyl, 2-chloroethyl, 1-chloropropyl, 2-chloropropyl, 3-chloropropyl, 4-chlorobutyl, 5-chloropentyl, 6-chlorohexyl, bromomethyl, 1-bromoethyl, 2-bromoethyl, 1-bromopropyl, 2-bromopropyl, 3-bromopropyl, 4-bromobutyl, 5-bromopentyl, 6-bromohexyl, iodomethyl, 1-iodoethyl, 2-iodoethyl, 1-iodopropyl, 2-iodopropyl, 3-iodopropyl, 4-iodobutyl, 5-iodopentyl, 6-iodohexyl, trifluoromethyl, 2,2,2-trifluoroethyl, trichloromethyl, 2,2,2-chloroethyl tribromomethyl, triuodomethyl, or the like.
Examples of preferable xe2x80x9caminoalkylaminoxe2x80x9d and xe2x80x9caminoalkylaminoxe2x80x9d moiety in xe2x80x9coptionally substituted with aminoalkylaminoxe2x80x9d are aminomethylamino, aminoethylamino, aminopropylamino, aminoisopropylamino, aminobutylamino, aminoisobutylamino, amino-tert-butylamino, aminopentylamino, aminohexylamino, di(aminomethyl)amino, di(aminoethyl)amino, di(aminopropyl)amino, di(aminoisopropyl)amino, di(aminobutyl)amino, di(aminoisobutyl)amino, di(amino-tert-butyl)amino, di(aminopentyl)amino, di(aminohexyl)amino or the like.
Suitable xe2x80x9cN-containing heterocyclic groupxe2x80x9d and xe2x80x9cN-containing heterocyclic groupxe2x80x9d moiety in xe2x80x9coptionally substituted with N-containing heterocyclic groupxe2x80x9d include ones containing N atom(s) from among those exemplified above with regard to xe2x80x9cheterocyclic groupxe2x80x9d.
Suitable xe2x80x9cprotected hydroxyxe2x80x9d includes hydroxy protected by a conventional protective group, for example, substituted lower alkoxy such as lower alkoxy(lower)alkoxy (e.g. methoxymethoxy), lower alkoxy(lower)alkoxy(lower)alkoxy (e.g. methoxyethoxymethoxy) and substituted or unsubstituted aryl(lower)alkoxy (e.g. benzyloxy, nitrobenzyloxy); acyloxy such as lower alkanoyloxy (e.g. acetoxy, propionyloxy, pivaloyloxy), aroyloxy (e.g. benzoyloxy, fluorenecarbonyloxy), lower alkoxycarbonyloxy (e.g. methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, tert-butoxycarbonyloxy, pentyloxycarbonyloxy, hexyloxycarbonyloxy), substituted or unsubstituted aryl(lower)alkoxycarbonyloxy (e.g. benzyloxy-carbonyloxy, bromobenzyloxycarbonyloxy), arenesulfonyloxy (e.g. benzenesulfonyloxy, tosyloxy) and alkanesulfonyloxy (e.g. methanesulfonyloxy, ethanesulfonyloxy); tri(lower)alkylsilyloxy (e.g. trimethylsilyloxy); tetrahydropyranyloxy; and the like.
Examples of preferable xe2x80x9cheterocyclic groupxe2x80x9d defined for A of the formula (I) are substituted or unsubstituted 1H-benzimidazol-4-yl such as 2-methyl-1-tert-butoxycarbonyl-1H-benzimidazol-4-yl, 2-methyl-1H-benzimidazol-4-yl, 2-phthaloylaminomethyl-1H-benzimidazol-4-yl, 2-aminomethyl-1H-benzimidazol-4-yl, 2-dimethylaminomethyl-1H-benzimidazol-4-yl, 2-methanesulfonylaminomethyl-1H-benzimidazol-4-yl, 2-(morpholin-4-yl)methyl-1H-benzimidazol-4-yl, 2-(4-tert-butoxycarbonylpiperazin-1-yl)methyl-1H-benzimidazol-4-yl, 2-(piperazin-1-yl) methyl-1H-benzimidazol-4-yl, 2-tert-butyldimethylsiloxymethyl-1H-benzimidazol-4-yl, 2-hydroxymethyl-1H-benzimidazol-4-yl, 2-(imidazol-1-yl)-1H-benzimidazol-4-yl, 2-tert-butoxycarbonylamino-1H-benzimidazol-4-yl, 2-amino-1H-benzimidazol-4-yl, 2-acetamido-1H-benzimidazol-4-yl, 2-methylsulfonylamino-1H-benzimidazol-4-yl, 2-trifluoromethyl-1H-benzimidazol-4-yl, 1,2-dimethyl-1H-benzimidazol-4-yl, 2-dimethylamino-1H-benzimidazol-4-yl, 1H-benzimidazol-4-yl, 2-methoxy-1H-benzimidazol-4-yl, 2-methoxymethyl-1H-benzimidazol-4-yl, 2-ethyl-1H-benzimidazol-4-yl, 1-tert-butoxycarbonyl-2-[2-(N-methyl-N-tert-butoxycarbonylamino)ethylamino]-1H-benzimidazol-4-yl, 2-[2-(methylamino)ethylamino]-1H-benzimidazol-4-yl, 2-n-propyl-1H-benzimidazol-4-yl, 2-(4-methylpiperazin-1-yl)-1H-benzimidazol-4-yl, 2-[N-[2-(dimethylamino)ethyl]-N-methylamino]-1H-benzimidazol-4-yl, 2-[2-(dimethylamino)ethylamino]-1H-benzimidazol-4-yl, 2-(morpholin-4-yl)-1H-benzimidazol-4-yl, 2-(imidazol-1-yl)methyl-1H-benzimidazol-4-yl, 2-[4-(dimethylamino)piperidin-1-yl]-1H-benzimidazol-4-yl, 2-(N,N-dimethylcarbamoyl)-1H-benzimidazol-4-yl, 1-tert-butoxycarbonyl-2-[N-(2-tert-butoxycarbonylaminoethyl)-N-methylamino]-1H-benzimidazol-4-yl and 2-[N-(aminoethyl)-N-methylamino]-1H-benzimidazol-4-yl;
substituted or unsubstituted 3H-benzimidazol-4-yl such as 2,3-dimethyl-3H-benzimidazol-4-yl;
substituted or unsubstituted benzoxazol-4-yl such as 2-methylbenzoxazol-4-yl; and
substituted or unsubstituted 1H-indazol-7-yl.
xe2x80x9cCondensed ring groupxe2x80x9d defined for B of the formula (I) may be saturated or unsaturated. Unsaturated condensed ring group includes partly unsaturated condensed ring group.
Suitable xe2x80x9csubstituent(s)xe2x80x9d in xe2x80x9ccondensed ring groupxe2x80x9d defined for B of the formula (I) include lower alkyl, halogen, hydroxy, N-protective group, xe2x95x90O and xe2x95x90CH2.
Suitable xe2x80x9clower alkylxe2x80x9d and xe2x80x9cN-protective groupxe2x80x9d are the same as those defined above with regard to the substituents of xe2x80x9cheterocyclic groupxe2x80x9d.
Suitable xe2x80x9chalogenxe2x80x9d includes fluoro, chloro, bromo and iodo.
Examples of preferable xe2x80x9csaturated or unsaturated condensed ring groupxe2x80x9d defined for B of the formula (I) are unsaturated benzazepinyl such as 2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl, 2,3,4,5-tetrahydro-5-oxo-1H-1-benzazepin-1-yl, 2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl, 2,3,4,5-tetrahydro-5-methylene-1H-1-benzazepin-1-yl, 2,3,4,5-tetrahydro-7-methyl-1H-1-benzazepin-1-yl, 2,3,4,5-tetrahydro-7-chloro-1H-1-benzazepin-1-yl and 2,3,4,5-tetrahydro-9-methyl-1H-1-benzazepin-1-yl;
unsaturated benzodiazepinyl such as 2,3,4,5-tetrahydro-4-oxo-1H-1,5-benzodiazepin-1-yl, 2,3,4,5-tetrahydro-5-oxo-1H-1,4-benzodiazepin-1-yl, 3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-1,3-benzodiazepin-1-yl and 4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-1-yl;
unsaturated pyridoazepinyl such as 6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-9-yl, 2,3,4,5-tetrahydro-1H-pyrido[3,4-b]azepin-1-yl, 2-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-5-yl and 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]azepin-1-yl;
unsaturated pyridodiazepinyl such as 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-1-yl;
unsaturated thienoazepinyl such as 2,3-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-b]azepin-8-yl and 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-4-yl;
unsaturated benzoxazepinyl such as 2,3,4,5-tetrahydro-1,5-benzoxazepin-5-yl and 1,2,3,5-tetrahydro-4,1-benzoxazepin-1-yl;
unsaturated benzothiazepinyl such as 2,3,4,5-tetrahydro-1,5-benzothiazepin-5-yl, 1-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-5-yl, 1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-5-yl, 1,2,3,5-tetrahydro-4,1-benzothiazepin-1-yl, 4-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-1-yl and 4,4-dioxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-1-yl;
unsaturated imidazobenzazepinyl such as 2-methyl-1,4,5,6-tetrahydro-imidazo[4,5-d][1]benzazepin-6-yl;
unsaturated pyridobenzoxazepinyl such as 5,6-dihydro-pyrido[2,3-b][1,5]benzoxazepin-6-yl; and
substituted indolinyl such as 3,3-dimethylindolin-1-yl.
The processes for preparing the object compound of the present invention are explained in detail in the following.
The object compound (I) or a salt thereof can be prepared by reacting a compound (III) or its reactive derivative at the carboxyl group or a salt thereof, with a compound (IV) or its reactive derivative at the amino group or a salt thereof.
Suitable salts of the compounds (III) and (IV) may be the same as those exemplified above with regard to the compound (I).
Suitable reactive derivative at the carboxy group of the compound (III) includes an acid halide, an acid anhydride, an activated amide and an activated ester. Examples of suitable reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (e.g. methanesulfonic acid), aliphatic carboxylic acid (e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid), or aromatic carboxylic acid (e.g. benzoic acid); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H-benzotriazole; or an activated ester (e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)2N+xe2x95x90CHxe2x80x94] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester) or an ester with a N-hydroxy compound (e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole). These reactive derivatives can optionally be selected according to the kind of the compound (III) to be used.
Suitable salts of the compound (III) and its reactive derivative can be referred to the ones as exemplified for the compound (I).
Suitable reactive derivative at the amino group of the compound (IV) includes Schiff""s base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (IV) with a carbonyl compound such as aldehyde or ketone; a silyl derivative formed by the reaction of the compound (IV) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide or bis(trimethylsilyl)urea; and a derivative formed by reaction of the compound (IV) with phosphorus trichloride or phosgene.
Suitable salts of the compound (IV) and its reactive derivative can be referred to the ones as exemplified for the compound (I).
The reaction is usually carried out in a conventional solvent such as water, an alcohol (e.g. methanol, ethanol), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylacetamide, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.
In this reaction, when the compound (III) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide; N-cyclohexyl-Nxe2x80x2-morpholinoethylcarbodiimide; N-cyclohexyl-Nxe2x80x2-(4-diethylaminocyclohexyl)carbodiimide; N,Nxe2x80x2-diethylcarbodiimide; N,Nxe2x80x2-diisopropylcarbodiimide; N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide; N,Nxe2x80x2-carbonylbis-(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; phosphorus pentachloride; thionyl chloride; mesyl chloride; oxalyl chloride; lower alkyl haloformate (e.g. ethyl chloroformate, isopropyl chloroformate); triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl) isoxazolium hydroxide intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; or so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride or methanesulfonyl chloride.
The reaction may also be carried out in the presence of an inorganic or organic base such as alkali metal carbonates, alkali metal hydrogencarbonates, tri(lower)alkylamine, pyridide, N-(lower)alkylmorpholine or N,N-di(lower)alkylbenzylamine.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
The object compound (Ib) or a salt thereof can be prepared by subjecting a compound (Ia) or a salt thereof to elimination reaction of the N-protective group in Axe2x80x2 and/or Bxe2x80x2.
Suitable salts of the compounds (Ia) and (Ib) may be the same as those exemplified above with regard to the compound (I).
This reaction is carried out in accordance with a conventional method such as hydrolysis or reduction.
The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
Suitable base includes, for example, inorganic bases such as alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (e.g. magnesium hydroxide, calcium hydroxide), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate), alkaline earth metal carbonates (e.g. magnesium carbonate, calcium carbonate), alkali metal hydrogencarbonates (e.g. sodium hydrogencarbonate, potassium hydrogencarbonate); and organic bases such as trialkylamines (e.g. trimethylamine, triethylamine), picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, and 1,8-diazabicyclo[5.4.0]undec-7-ene.
Suitable acid includes organic acids (e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid) and inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid).
The elimination using Lewis acid such as trihaloacetic acid (e.g. trichloroacetic acid, trifluoroacetic acid) is preferably carried out in the presence of cation trapping agents (e.g. anisole, phenol).
The reaction is usually carried out in a solvent such as water, an alcohol (e.g. methanol, ethanol), methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The reaction method applicable to the elimination reaction includes chemical reduction and catalytic reduction.
Suitable reducing agent to be used in chemical reduction is a combination of a metal (e.g. tin, zinc, iron) or metallic compound (e.g. chromium chloride, chromium acetate) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid).
Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire), palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel), cobalt catalysts (e.g. reduced cobalt, Raney cobalt), iron catalysts (e.g. reduced iron, Raney iron) and copper catalysts (e.g. reduced copper, Raney copper, Ullman copper).
The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, methanol, ethanol, propanol, N,N-dimethylformamide, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvents, and other conventional solvents such as diethyl ether, dioxane and tetrahydrofuran, or a mixture thereof.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
The object compound (Id) or a salt thereof can be prepared by subjecting a compound (Ic) or a salt thereof to reduction of xe2x95x900 in B3.
Suitable salts of the compounds (Ic) and (Id) may be the same as those exemplified above with regard to the compound (I).
This reaction is carried out in accordance with a conventional method using a reducing agent.
Suitable reducing agent includes alkali metal borohydride (e.g. sodium borohydride, sodium cyanoborohydride).
The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, alcohol (e.g. methanol, ethanol, propanol), or a mixture thereof.
The reaction temperature of this reaction is not critical and the reaction is usually carried out under cooling to warming.
The object compound (If) or a salt thereof can be prepared by subjecting a compound (Ie) or a salt thereof to hydrolysis.
Suitable salts of the compounds (Ie) and (If) may be the same as those exemplified above with regard to the compound (I).
This reaction is carried out in accordance with a conventional method using a base or an acid including Lewis acid.
Suitable base includes an inorganic or organic base such as alkaline metals (e.g. sodium, potassium), alkaline earth metals (e.g. magnesium, calcium), hydrides thereof, hydroxides thereof, carbonate salts thereof, bicarbonate salts thereof, alkylamine (e.g. methylamine, trimethylamine, triethylamine), picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene.
Suitable acid includes organic acids (e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid), inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride) and acid addition salt compounds (e.g. pyridine hydrochloride).
The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, dioxane, alcohol (e.g. methanol, ethanol, propanol), acetonitrile, tetrahydrofuran, acetic acid, N,N-dimethylformamide, or a mixture thereof.
The reaction temperature of this reaction is not critical and the reaction is usually carried out under cooling to warming.
The object compound (Ih) or a salt thereof can be prepared by reacting a compound (Ig) or a salt thereof with an alkylating agent.
Suitable salts of the compounds (Ig) and (Ih) may be the same as those exemplified above with regard to the compound (I).
This reaction is carried out in accordance with a conventional method using a conventional alkylating agent.
Suitable alkylating agent includes lower alkyl halides (e.g. methyl iodide, ethyl iodide); combination of carbonyl compounds such as aliphatic ketones (e.g. acetone, ethylmethylketone), carboaldehydes (e.g. formaldehyde, ethanal) and orthocarbonates (e.g. orthoformate), and reducting agents such as formic acid, sodium borohydride, sodium cyanoborohydride, palladium-carbon used in chemical reduction or catalytic reduction.
In case that a lower alkyl halide is used as an alkylating agent, the reaction may preferably be carried out in the presence of alkaline metals (e.g. sodium, potassium), alkaline earth metals (e.g. magnesium, calcium), hydride thereof, hydroxide thereof, carbonate salts thereof, bicarbonate salts thereof, and organic base (e.g. tri(lower)alkylamine, N,N-di(lower)alkylaniline).
The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, dioxane, alcohol (e.g. methanol, ethanol, propanol), acetonitrile, tetrahydrofuran, acetic acid, N,N-dimethylformamide, or a mixture thereof.
Additionally, in case that the above-mentioned alkylating agent or base to be used in the reaction are liquid, they can also be used as a solvent.
The reaction temperature of this reaction is not critical and the reaction is usually carried out under cooling to warming.
The object compound (Ii) or a salt thereof can be prepared by reacting a compound (Ig) or a salt thereof with an acylating agent.
Suitable salts of the compounds (Ig) and (Ii) may be the same as those exemplified above with regard to the compound (I).
This reaction is carried out in accordance with a conventional method using a conventional acylating agent.
Suitable acylating agent includes an organic acid represented by the formula: Rxe2x80x2xe2x80x94OH wherein Rxe2x80x2 is acyl or substituted acyl as illustrated above, or its reactive derivative.
Suitable organic acid derivative includes conventional ones such as acid halides (e.g. acid chlorides, acid bromides), acid azides, acid anhydrides, activated amides and activated esters.
In case that acylating agent is used in a free acid form or its salt form, the acylation may preferably be carried out in the presence of a conventional condensing agent as explained in Process 1.
The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, acetone, dioxane, chloroform, methylene chloride, acetonitrile, ethylene chloride, tetrahydrofuran, acetic acid, N,N-dimethylform-amide, pyridine, or a mixture thereof.
Additionally, the reaction may preferably be carried out in the presence of a conventional base such as triethylamine, pyridine and sodium hydroxide.
The reaction temperature of this reaction is not critical and the reaction is usually carried out under cooling to warming.
The object compound (Ik) or a salt thereof can be prepared by subjecting a compound (Ij) or a salt thereof to elimination reaction of the hydroxy-protective group in A8.
Suitable salts of the compounds (Ij) and (Ik) may be the same as those exemplified above with regard to the compound (I).
This reaction can be carried out in substantially the same manner as in Process 2, and therefore, the reaction mode and reaction conditions (e.g. base, acid, catalyst, solvent, reaction temperature) of this reaction are to be referred to those explained in Process 2.
The object compound (Im) or a salt thereof can be prepared by subjecting a compound (Il) or a salt thereof to oxidation of S atom in B5. The object compound (In) or a salt thereof can be prepared by subjecting a compound (Im) or a salt thereof to oxidation of S atom in B6.
Suitable salts of the compounds (Il), (Im) and (In) may be the same as those exemplified above with regard to the compound (I).
This reaction is carried out in accordance with a conventional method using an oxidizing agent.
Suitable oxidizing agent includes hydrogen peroxide, Jones reagent, peracids (e.g. peracetic acid, perbenzoic acid, m-chloroperbenzoic acid), chromic acid, potassium permanganate, and alkali metal periodates (e.g. sodium periodate).
The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, organic acid (e.g. acetic acid, trifluoroacetic acid), acetone, ethyl acetate, alcohol (e.g. methanol, ethanol), dichloromethane, chloroform, or a mixture thereof.
The reaction temperature of this reaction is not critical and the reaction is usually carried out under cooling to warming.
The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation or the like.
The object compound (I) thus obtained can be converted to a pharmaceutically acceptable salt in a conventional manner.
It is to be noted that the object compound (I) may include one or more stereoisomer(s) such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) or double bond(s), and all such isomers and mixtures thereof are included within the scope of this invention.
The object compound (I) and pharmaceutically acceptable salts of the present invention exhibit activities such as vasopressin antagonistic activity, vasodilating activity, hypotensive activity, activity of inhibiting saccharide release in liver, activity of inhibiting growth of mesangium cells, diuretic activity, platelet aggregation inhibitory activity, oxytocin antagonistic activity, antidepressant activity, antianxiety activity and the like, and are useful for the treatment and/or prophylaxis of hypertension, heart failure, renal insufficiency, edema, ascites, vasopressin parasecretion syndrome, hepatocirrhosis, hyponatremia, hypokalemia, diabetes mellitus, circulation disorder, cerebrovascular disease (e.g. cerebral edema, cerebral infarction, etc.), Meniere""s syndrome (e.g. Meniere""s disease, etc.), motion sickness, depressant, anxiety and the like in human beings and animals.
In order to illustrate the usefulness of the object compound (I), the pharmacological data of the compound (I) are shown in the following.
Vasopressin 1 (VI) Receptor Binding
(i) Test Method
Blood was obtained from normal subject by venipuncture. Platelet-rich plasma (PRP) was prepared by centrifugation of whole blood at 200xc3x97g for 10 minutes. PRP was centrifuged at 45,000xc3x97g for 30 minutes. The remaining pellet was resuspended in 10 volume of ice-cold 100 mM Tris-HCl buffer (pH 7.4, containing 5 mM MgCl2, 0.1% bovine serum albumin and 1 mM EDTA), and again centrifuged at 45,000xc3x97g for 30 minutes. The final pellet was resuspended in 100 mM Tris-HCl buffer. The resulting suspension was used immediately for the binding assay.
Competition assays were conducted at equilibrium (15 minutes at 30xc2x0 C.) by using 1.5 nM 3H-vasopressin (40-87 Ci/mmol; New England Nuclear) in 100 mM Tris-HCl buffer (pH 7.4). Nonspecific binding was determined by using 1 xcexcM vasopressin. After incubation, the reaction was terminated by adding 5 ml of ice-cold 100 mM Tris-HCl buffer (pH 7.4), and then filtered immediately through Whatman glass filter (GF/C). The filter was washed twice with the same buffer. The glass filter was placed in a liquid scintillation cocktail, and the radioactivity thereof was counted by using a liquid scintillation counter. Competition activity of the test compound was represented by IC50 values.
(ii) Test Result
Vasopressin 2 (V2) Receptor Binding
(i) Test Method
For binding assays, a receptor cDNA was permanently expressed in Chinese hamster ovary (CHO) cells. A vector directing expression of the cDNA of a human V2 receptor was transfected into the CHO cells, and the clonal cell lines expressing the human V2 receptor were established essentially as described previously (Nakajima, Y., et. al. J. Biol. chem., 267, 2437, 1992).
DNA-transfected cells were harvested and homogenized in ice-cold 250 nm Tris-HCl (pH 7.4), 10 mM MgCl2, 1 mM EDTA and 5 xcexcg/ml p-amidinophenylmethylsulfonyl fluoride (A-PMSF). The homogenate was centrifuged at 500xc3x97g for 10 minutes. The supernatant was centrifuged at 100,00xc3x97g for 1 hour. The final pellet was suspended in 25 mM Tris-HCl buffer (pH 7.4, containing 10 mM MgCl2, 1 mM EDTA and 5 xcexcg/ml A-PMSF), and stored in small aliquots at xe2x88x9280xc2x0 C.
Competition assays were conducted at equilibrium (2 hours at 22xc2x0 C.) by using 0.5 nm 3H-vasopressin (40-87 Ci/mmol; New England Nuclear) in 100 mM Tris-HCl buffer (pH 7.4, containing 5 mM MgCl2, 5 xcexcg/ml A-PMSF, 4 xcexcg/ml leupeptin, 40 xcexcg/ml bacitracin, 20 xcexcg/ml chymostatin and 0.1% bovine serum albimin). Nonspecific binding was determined by using 1 xcexcM vasopressin. After incubation, the reaction mixture was immediately filtered through Whatman glass filter (GF/C). The filter was washed twice with the same buffer. The radioactivity was counted by using a liquid scintillation counter. Competition activity of the test compound was represented by IC50 values.
(ii) Test Result
For therapeutic purposes, the compound (I) or pharmaceutically acceptable salts threrof of the present invention can be used in the form of pharmaceutical preparation containing compound (I) or pharmaceutical acceptable salts threrof, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid, semi-solid or liquid excipient suitable for oral, parenteral or external (topical) administration. The pharmaceutical preparation may be in the form of capsules, tablets, dragees, granules, suppositories, solution, lotion, suspension, emulsion, ointment, gel, or the like. If desired, there may be included, in these preparations, auxiliary substances, stabilizing agent, wetting or emulsifying agent, buffer and other commonly used additives.
While the dosage of the compound (I) or pharmaceutically acceptable salts threrof will vary depending upon the age and condition of patients, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg or 1000 mg of the compound (I) may be effective for treating the above-mentioned diseases. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.